EP1775347A2 - Verfahren zur enantiomeren Trennung von 1-substituierten-2-(Aminomethyl)-Pyrrolidinen durch Amidierung mit Lipase - Google Patents
Verfahren zur enantiomeren Trennung von 1-substituierten-2-(Aminomethyl)-Pyrrolidinen durch Amidierung mit Lipase Download PDFInfo
- Publication number
- EP1775347A2 EP1775347A2 EP06021182A EP06021182A EP1775347A2 EP 1775347 A2 EP1775347 A2 EP 1775347A2 EP 06021182 A EP06021182 A EP 06021182A EP 06021182 A EP06021182 A EP 06021182A EP 1775347 A2 EP1775347 A2 EP 1775347A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- amine
- configuration
- aminomethyl
- substituted
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 0 *N1C(CN)CCC1 Chemical compound *N1C(CN)CCC1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
- C12P41/007—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures by reactions involving acyl derivatives of racemic amines
Definitions
- the present invention relates to a process for the enantiomeric resolution of 1-substituted 2-(aminomethyl)pyrrolidines by amidation in the presence of lipases.
- Optically active 1-substituted 2-(aminomethyl)pyrrolidines are useful intermediates for the preparation of pharmaceutical active ingredients, in particular for the preparation of Levosulpiride and enantiomerically pure forms of similar medicaments, such as Sultopride and Amilsulpiride.
- Levosulpiride of formula (II) reported below, specifically requires 2-(aminomethyl)-1-ethyl-pyrrolidine of S configuration as intermediate.
- the process of the invention characterized by the use of microbial lipases, provides the desired enantiomer of S configuration with enantioselectivity higher than 95%, preferably higher than 99%.
- the process of the invention comprises the reaction of the racemic amine with benzyl acetate in acetonitrile in the presence of a lipase selected from Pseudomonas cepacia, Pseudomonas fluorescens or Candida rugosa lipases, to give the corresponding 1-substituted N-(pyrrolidin-2-yl-methyl)-acetamides of formula (II), with R configuration, and the residual amine with (S) configuration.
- a lipase selected from Pseudomonas cepacia, Pseudomonas fluorescens or Candida rugosa lipases
- acylating agents such as trifluoroethyl butyrate, ethyl butyrate, allyl butyrate, diallyl carbonate, methyl mandelate, methylphenyl acetate and solvents such as isopropyl ether, tert-butyl methyl ether, octane, dioxane, always give unsatisfactory results.
- the process according to the invention is preferably carried out at room temperature, for times ranging from 48 to 172 hours.
- Enzymes from Pseudomonas cepacia, Pseudomonas fluorescens or Candida rugosa are commercially available and, as a rule, they are used in amounts ranging from 300 to 1000 units per g of substrate. If desired, said enzymes can be bound to suitable supports, according to conventional techniques.
- the invention relates to a process for the preparation of Levosulpiride, which comprises the resolution of 2-(aminomethyl)-1-ethyl pyrrolidine by reacting the racemic amine with benzyl acetate in acetonitrile in the presence of a lipase selected from Pseudomonas cepacia, Pseudomonas fluorescens or Candida rugosa lipases, to give the corresponding N-(pyrrolidin-2-yl-methyl)-1-ethyl acetamide, with R configuration, and the residual amine with S configuration which is isolated and purified by distillation.
- a lipase selected from Pseudomonas cepacia, Pseudomonas fluorescens or Candida rugosa lipases
- the pure amine with S configuration is then converted to Levosulpiride by reaction with a 2-methoxy-5-sulfamoylbenzoic acid derivative such as methyl 2-methoxy-5-sulfamoylbenzoate in alcohols such as methanol, ethanol, propanol or butanol at a temperature ranging from 20°C to the reflux temperature of the solvent, and subsequent purification according to known techniques such as extractions and/or crystallizations.
- a 2-methoxy-5-sulfamoylbenzoic acid derivative such as methyl 2-methoxy-5-sulfamoylbenzoate
- alcohols such as methanol, ethanol, propanol or butanol
- subsequent purification according to known techniques such as extractions and/or crystallizations.
- PFL Pseudomonas fluorescens
- PCL Pseudomonas cepacia
- CTL Candida rugosa
- samples were taken at different times, then centrifuged to remove the enzyme, and the conversion degree of the amine to amide was evaluated by GC analysis of the supernatant from centrifugation.
- the conversion degree was calculated using the values of the areas of the two peaks of the starting product and the acetylated product, respectively.
- reaction mixture was analyzed by HPLC analysis, to evaluate the optical purity of the residual amine, according to the procedure reported in the following:
- reaction sample was evaporated to dryness under nitrogen, then the residue was redissolved in ethanol to a final concentration of about 100 mg/ml. 20 ⁇ l of this solution was injected on a CHIRALPAK ADH column 250 x 4.6 mm using an n-hexane-absolute ethanol-diethylamine 80:20:0.75 mixture as a mobile phase with flow of 1.0 ml/min and UV detector set at 220 nm.
- Results were expressed as peaks area percentages, only considering the peaks of the two enantiomers.
- reaction mixture was evaporated to dryness and (S)-2-(aminomethyl)-1-ethylpyrrolidine was isolated and purified by distillation under vacuum, collecting the fractions between 40 and 45°C at 10 mmHg.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Analytical Chemistry (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT001943A ITMI20051943A1 (it) | 2005-10-14 | 2005-10-14 | Processo di risoluzione anantiomerica di 2-aminometil-pirrolidine 1-sostitute per ammidazione in presenza di lipasi |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1775347A2 true EP1775347A2 (de) | 2007-04-18 |
EP1775347A3 EP1775347A3 (de) | 2007-07-25 |
Family
ID=37685917
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP06021182A Withdrawn EP1775347A3 (de) | 2005-10-14 | 2006-10-09 | Verfahren zur enantiomeren Trennung von 1-substituierten-2-(Aminomethyl)-Pyrrolidinen durch Amidierung mit Lipase |
Country Status (3)
Country | Link |
---|---|
US (1) | US20070105201A1 (de) |
EP (1) | EP1775347A3 (de) |
IT (1) | ITMI20051943A1 (de) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103804265A (zh) * | 2012-11-08 | 2014-05-21 | 江苏天士力帝益药业有限公司 | 一种舒必利或其光学异构体的合成及后处理方法 |
CN105837485A (zh) * | 2015-01-16 | 2016-08-10 | 王志训 | 一种(S)-l-乙基-2-氨甲基吡咯烷的工业制造方法 |
WO2018048943A1 (en) * | 2016-09-07 | 2018-03-15 | Pharmakea, Inc. | Crystalline forms of a lysyl oxidase-like 2 inhibitor and methods of making |
US11072585B2 (en) | 2015-03-06 | 2021-07-27 | Pharmakea, Inc. | Fluorinated lysyl oxidase-like 2 inhibitors and uses thereof |
US11793797B2 (en) | 2016-09-07 | 2023-10-24 | Pharmakea, Inc. | Uses of a lysyl oxidase-like 2 inhibitor |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2014990A (en) * | 1978-02-16 | 1979-09-05 | Ravizza Spa | Process for preparing an optically active benzamide, the optically active benzamide so obtained and pharmaceutical compositions containing it |
US5300660A (en) * | 1986-05-22 | 1994-04-05 | Astra Lakemedel Aktiebolag | Efficient stereoconservative synthesis of 1-substituted (S)- and (R)-2-aminomethylpyrrolidines and intermediates thereto |
US6214608B1 (en) * | 1995-02-03 | 2001-04-10 | Basf Aktiengesellschaft | Resolution of racemates of primary and secondary heteroatom-substitued amines by enzyme-catalyzed acylation |
-
2005
- 2005-10-14 IT IT001943A patent/ITMI20051943A1/it unknown
-
2006
- 2006-10-09 EP EP06021182A patent/EP1775347A3/de not_active Withdrawn
- 2006-10-12 US US11/548,804 patent/US20070105201A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2014990A (en) * | 1978-02-16 | 1979-09-05 | Ravizza Spa | Process for preparing an optically active benzamide, the optically active benzamide so obtained and pharmaceutical compositions containing it |
US5300660A (en) * | 1986-05-22 | 1994-04-05 | Astra Lakemedel Aktiebolag | Efficient stereoconservative synthesis of 1-substituted (S)- and (R)-2-aminomethylpyrrolidines and intermediates thereto |
US6214608B1 (en) * | 1995-02-03 | 2001-04-10 | Basf Aktiengesellschaft | Resolution of racemates of primary and secondary heteroatom-substitued amines by enzyme-catalyzed acylation |
Non-Patent Citations (4)
Title |
---|
ADAMCZYK M ET AL: "Pseudomonas cepacia Lipase Mediated Amidation of Benzyl Esters" TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 37, no. 44, 28 October 1996 (1996-10-28), pages 7913-7916, XP004031004 ISSN: 0040-4039 * |
ADAMCZYK M ET AL: "Regioselective Pseudomonas cepacia lipase mediated amidations of benzyl esters with diamines" TETRAHEDRON: ASYMMETRY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 8, no. 13, 10 July 1997 (1997-07-10), pages 2099-2100, XP004083202 ISSN: 0957-4166 * |
ALFONSO I ET AL: "SEQUENTIAL BIOCATALYTIC RESOLUTION OF (PLUS OR MINUS)-TRANS-CYCLOHEXANE-1,2-DIAMINE. CHEMOENZYMATIC SYNTHESIS OF AN OPTICALLY ACTIVE POLYAMINE" CHEMICAL COMMUNICATIONS - CHEMCOM, ROYAL SOCIETY OF CHEMISTRY, GB, no. 21, 1996, pages 2471-2472, XP000952857 ISSN: 1359-7345 * |
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1996, JIANG ZHONG-LIANG LUAN JIA-GUO ET AL: "Synthesis of levosulpiride" XP002437988 Database accession no. PREV199799461472 -& ZHONGGUO YIYAO GONGYE ZAZHI, vol. 27, no. 11, 1996, pages 485-486, XP009008934 ISSN: 1001-8255 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103804265A (zh) * | 2012-11-08 | 2014-05-21 | 江苏天士力帝益药业有限公司 | 一种舒必利或其光学异构体的合成及后处理方法 |
CN103804265B (zh) * | 2012-11-08 | 2018-08-07 | 江苏天士力帝益药业有限公司 | 一种舒必利或其光学异构体的合成及后处理方法 |
CN105837485A (zh) * | 2015-01-16 | 2016-08-10 | 王志训 | 一种(S)-l-乙基-2-氨甲基吡咯烷的工业制造方法 |
US11072585B2 (en) | 2015-03-06 | 2021-07-27 | Pharmakea, Inc. | Fluorinated lysyl oxidase-like 2 inhibitors and uses thereof |
WO2018048943A1 (en) * | 2016-09-07 | 2018-03-15 | Pharmakea, Inc. | Crystalline forms of a lysyl oxidase-like 2 inhibitor and methods of making |
CN109983006A (zh) * | 2016-09-07 | 2019-07-05 | 法玛克亚公司 | 赖氨酰氧化酶样2抑制剂的结晶形式及其制备方法 |
US10774069B2 (en) | 2016-09-07 | 2020-09-15 | Pharmakea, Inc. | Crystalline forms of a lysyl oxidase-like 2 inhibitor and methods of making |
CN109983006B (zh) * | 2016-09-07 | 2022-02-25 | 法玛克亚公司 | 赖氨酰氧化酶样2抑制剂的结晶形式及其制备方法 |
US11459309B2 (en) | 2016-09-07 | 2022-10-04 | Pharmakea, Inc. | Crystalline forms of a lysyl oxidase-like 2 inhibitor and methods of making |
US11793797B2 (en) | 2016-09-07 | 2023-10-24 | Pharmakea, Inc. | Uses of a lysyl oxidase-like 2 inhibitor |
Also Published As
Publication number | Publication date |
---|---|
US20070105201A1 (en) | 2007-05-10 |
ITMI20051943A1 (it) | 2007-04-15 |
EP1775347A3 (de) | 2007-07-25 |
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